Updated pharmacodynamic and safety data from SUNFISH Part 1, a study evaluating the oral SMN2 splicing modifier RG7916 in patients with Type 2 or 3 spinal muscular atrophy (P4.453)

Objective: SUNFISH (NCT02908685) study assesses the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of RG7916 in patients with Type 2 or Type 3 spinal muscular atrophy (SMA).

Background: SMA is characterized by motor neuron loss and muscle atrophy due to reduced levels of survival of motor neuron (SMN) protein. RG7916 is an orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing towards the production of full-length SMN2 mRNA and increases SMN protein levels.

Design/Methods: SUNFISH is a multicenter, double-blind, placebo-controlled trial (randomized 2:1, RG7916:placebo) in patients with Type 2 or 3 SMA aged 2–25 years. SUNFISH comprises two parts: Part 1 is evaluating the safety, tolerability and PK/PD of several RG7916 dose levels (n=51); the pivotal Part 2 is assessing the safety and efficacy of the RG7916 dose level selected from Part 1 (n=168).

Results: We have previously presented an early analysis of SUNFISH Part 1, which showed that RG7916 administration results in a dose-dependent increase in full-length SMN2 mRNA and a concomitant decrease in SMN2Δ7 mRNA. Recent analysis of SMN protein levels in whole blood showed that in patients with SMA, SMN protein increased in a dose-dependent manner up to median 2.5-fold. The safety, tolerability and PK/PD data from Part 1 informed the selection of a RG7916 dose level for SUNFISH Part 2 predicted to lead to clinically efficacious increases in SMN protein. To date, no drug-related adverse events leading to withdrawal have been observed.

We will provide a detailed SUNFISH update with novel biomarker, PK and full unblinded safety results from Part 1.

Conclusions: In SUNFISH Part 1, RG7916 treatment modulated SMN2 mRNA and increased SMN protein dose-dependently. The clinical benefit of the selected dose level is being assessed in SUNFISH Part 2, which is currently recruiting globally.

Study Supported by:

F. Hoffmann-La Roche

Disclosure: Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen MA, Inc, Ionis Pharmaceuticals, Inc. & F. Hoffman La-Roche Ltd. Dr. Baranello has nothing to disclose. Dr. Kirschner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Roche, Avexis. Dr. Kirschner has received research support from Biogen, Roche, Santhera, PTC. Dr. Servais has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Avexis, Sarepta, Dynacure, Pfizer, Servier. Dr. Servais has received research support from Roche, Valerion, Dynacure. Dr. Goemans has nothing to disclose. Dr. Pera has nothing to disclose. Dr. Marquet has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Armstrong has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Kletzl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Kletzl holds stock and/or stock options in Roche. Dr. Kletzl has received research support from Roche. Dr. Gerber has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Gerber holds stock and/or stock options in Roche. Dr. Czech has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Czech has received compensation for serving on the Board of Directors of F. Hoffmann-La Roche Ltd. Dr. Cleary has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche. Dr. Chan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Nave has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Gorni has nothing to disclose. Dr. Khwaja has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Khwaja holds stock and/or stock options in Roche, which sponsored research in which Dr. Khwaja was involved as an investigator. Dr. Khwaja has received research support from Roche.